Lieu Valerie H, Wu Josephine W, Wang Steven S-S, Wu Chia-Hung
Department of Chemical Engineering National Taiwan University, Taipei 10617, Taiwan.
Biotechnol Prog. 2007 May-Jun;23(3):698-706. doi: 10.1021/bp060353n. Epub 2007 May 11.
It has been reported that more than 20 different human proteins can fold abnormally, resulting in the formation of pathological deposits and several lethal degenerative diseases. Despite extensive investigations on amyloid fibril formation, the detailed molecular mechanism remained rather elusive. The current research, utilizing hen egg-white lysozymes as a model system, is aimed at exploring inhibitory activities of two potential molecules against lysozyme fibril formation. We first demonstrated that the formation of lysozyme amyloid fibrils at pH 2.0 was markedly enhanced by the presence of agitation in comparison with its quiescent counterpart. Next, via numerous spectroscopic techniques and transmission electron microscopy, our results revealed that the inhibition of lysozyme amyloid formation by either rifampicin or its analogue p-benzoquinone followed a concentration-dependent fashion. Furthermore, while both inhibitors were shown to acquire an anti-aggregating and a disaggregating activity, rifampicin, in comparison with p-benzoquinone, served as a more effective inhibitor against in vitro amyloid fibrillogenesis of lysozyme. It is our belief that the data reported in this work will not only reinforce the findings validated by others that rifampicin and p-benzoquinone serve as two promising preventive molecules against amyloid fibrillogenesis, but also shed light on a rational design of effective therapeutics for amyloidogenic diseases.
据报道，20多种不同的人类蛋白质会发生异常折叠，导致病理性沉积物的形成以及几种致命的退行性疾病。尽管对淀粉样纤维形成进行了广泛研究，但其详细的分子机制仍然相当难以捉摸。目前的研究以鸡蛋清溶菌酶作为模型系统，旨在探索两种潜在分子对溶菌酶纤维形成的抑制活性。我们首先证明，与静态条件相比，在pH 2.0时，搅拌会显著增强溶菌酶淀粉样纤维的形成。接下来，通过大量光谱技术和透射电子显微镜，我们的结果表明，利福平或其类似物对苯醌对溶菌酶淀粉样形成的抑制作用呈浓度依赖性。此外，虽然两种抑制剂都显示出具有抗聚集和解聚活性，但与对苯醌相比，利福平是更有效的溶菌酶体外淀粉样纤维生成抑制剂。我们相信，这项工作中报道的数据不仅会加强其他人验证的利福平和对苯醌作为两种有前景的抗淀粉样纤维生成预防分子的发现，还会为淀粉样变性疾病有效治疗药物的合理设计提供线索。
